TY - JOUR

T1 - Genome-wide association study in ethnic Russians suggests an association of the MHC class III genomic region with the risk of primary varicose veins

AU - Shadrina, Alexandra

AU - Tsepilov, Yakov

AU - Sokolova, Ekaterina

AU - Smetanina, Mariya

AU - Voronina, Elena

AU - Pakhomov, Eugene

AU - Sevost'ianova, Kseniya

AU - Shevela, Andrey

AU - Ilyukhin, Evgeny

AU - Seliverstov, Evgeny

AU - Zolotukhin, Igor

AU - Filipenko, Maxim

N1 - Publisher Copyright: © 2018 Elsevier B.V.

PY - 2018/6/15

Y1 - 2018/6/15

N2 - Heredity is a well-known risk factor for varicose veins, but genetic basis of this condition remains poorly studied. Our aim was to conduct a large-scale genetic association study for primary varicose veins (PVVs) in the population of ethnic Russians. An initial scan using Illumina HumanExome-12 v1.0 BeadChip was performed for 273 patients with PVVs and 250 controls without a history of chronic venous disease and other venous disorders. After quality control and removal of monomorphic markers, 25,424 common and 48,232 rare variants were included in the analysis. 42 single nucleotide polymorphisms (SNPs) were genotyped in the independent replication cohort of 447 PVVs patients and 443 controls. Association of common variants with PVVs was investigated by logistic regression, and the impact of rare variants was analyzed using sequence kernel association test. No effect of low frequency alleles has been revealed in our study. Common variant analysis identified a promising signal at chromosome 6 within classical major histocompatibility complex (MHC) class III subregion. The most strongly associated SNP in a combined analysis that reached a suggestive significance level of 3.2e−05 was polymorphism rs4151657 in the complement factor B gene. Testing for potential pleiotropy with other traits indicated that the same causal variant in this region increases the risk of rheumatoid arthritis and has a negative impact on human height. Our results provide suggestive evidence for the involvement of the MHC class III genes in the pathogenesis of PVVs. Further independent studies are needed to confirm our pilot findings.

AB - Heredity is a well-known risk factor for varicose veins, but genetic basis of this condition remains poorly studied. Our aim was to conduct a large-scale genetic association study for primary varicose veins (PVVs) in the population of ethnic Russians. An initial scan using Illumina HumanExome-12 v1.0 BeadChip was performed for 273 patients with PVVs and 250 controls without a history of chronic venous disease and other venous disorders. After quality control and removal of monomorphic markers, 25,424 common and 48,232 rare variants were included in the analysis. 42 single nucleotide polymorphisms (SNPs) were genotyped in the independent replication cohort of 447 PVVs patients and 443 controls. Association of common variants with PVVs was investigated by logistic regression, and the impact of rare variants was analyzed using sequence kernel association test. No effect of low frequency alleles has been revealed in our study. Common variant analysis identified a promising signal at chromosome 6 within classical major histocompatibility complex (MHC) class III subregion. The most strongly associated SNP in a combined analysis that reached a suggestive significance level of 3.2e−05 was polymorphism rs4151657 in the complement factor B gene. Testing for potential pleiotropy with other traits indicated that the same causal variant in this region increases the risk of rheumatoid arthritis and has a negative impact on human height. Our results provide suggestive evidence for the involvement of the MHC class III genes in the pathogenesis of PVVs. Further independent studies are needed to confirm our pilot findings.

KW - Association

KW - Genetics

KW - Russians

KW - Varicose veins

KW - Chromosomes, Human, Pair 6/genetics

KW - Genetic Predisposition to Disease

KW - Major Histocompatibility Complex

KW - Humans

KW - Middle Aged

KW - Varicose Veins/genetics

KW - Logistic Models

KW - Male

KW - Russia/ethnology

KW - Case-Control Studies

KW - Sequence Analysis, DNA/methods

KW - Young Adult

KW - Pilot Projects

KW - Genome-Wide Association Study/methods

KW - Aged, 80 and over

KW - Adult

KW - Female

KW - Aged

KW - Cohort Studies

UR - http://www.scopus.com/inward/record.url?scp=85044061644&partnerID=8YFLogxK

U2 - 10.1016/j.gene.2018.03.039

DO - 10.1016/j.gene.2018.03.039

M3 - Article

C2 - 29551506

AN - SCOPUS:85044061644

VL - 659

SP - 93

EP - 99

JO - Gene

JF - Gene

SN - 0378-1119

ER -